Stability of arsenic metabolites, arsenic triglutathione [As(GS)3] and methylarsenic diglutathione [CH3As(GS)2], in rat bile

Inorganic arsenicals such as arsenite (iAsIII) and arsenate (iAsV) are well-known human carcinogens. Arsenic is metabolized by repetitive reduction and oxidative methylation, and is excreted mainly in urine as monomethylated arsenicals (MMAs) and dimethylated arsenicals (DMAs). Recently, it has been shown that iAsIII administered intravenously or orally is excreted into bile as arsenic-glutathione (As-GSH) complexes such as arsenic triglutathione [As(GS)3] and methylarsenic diglutathione [CH3As(GS)2]. In order to carry out the speciation of As-GSH complexes, it is important to understand their stability. The present study was designed to clarify the stability of As-GSH complexes in rat bile, and the role of GSH in stabilizing these complexes. Arsenic species were separated on an anion-exchange column and were analyzed by high-performance liquid chromatography-inductively coupled argon plasma mass spectrometry (HPLC-ICP MS). As(GS)3 and CH3As(GS)2 were unstable in bile and were hydrolyzed to iAsIII and monomethylarsonous acid (MMAIII) in the absence of GSH. As(GS)3 appeared to be stable in the presence of 10 mM GSH. Exogenously added GSH also stabilized CH3As(GS)2 in bile at the concentrations of 5 mM or higher. It has been suggested that trivalent arsenicals, especially MMAIII, are more toxic than corresponding pentavalent ones. These results suggest that GSH plays an important role in preventing hydrolysis of As-GSH complexes and the generation of well-known toxic trivalent arsenicals.